Our current research interests are aimed toward examining the mechanism by which Eph receptor tyrosine kinases and their ephrin ligands signal events affecting cell-cell adhesion and morphogenetic movements. From the elucidation of these signal transduction pathways we may improve our understanding of oncogenesis. The cell-cell adhesion system plays a major role in normal development and morphogenesis. Inactivation of this adhesion system is thought to play a critical role in cancer invasion and metastasis. The Xenopus embryo is well suited for investigations of these processes because the frog has a well characterized and invariant cell fate map and cell lineage can be easily traced during experiments. Mutant receptors, ligands, and other proteins can be ectopically expressed in embryos. Thus, their effects on signal transduction, motility, and differentiation can be assessed morphologically and histologically as well as biochemically in a developing vertebrate. Our laboratory is currently investigating the role of the Xenopus Eph receptor tyrosine kinases and ephrinB transmembrane ligands in cell signaling and function using the Xenopus oocyte and embryo systems, as well as human cultured cell lines. At present, our emphasis is placed upon the mechanism by which these Eph family members send signals affecting morphogenetic movements. Members of the Eph family have been implicated in regulating numerous developmental processes and have been found to be de-regulated in metastatic cancers, for example, prostate, ovarian, breast, colon, neuroblastoma, lung, and melanoma.Our laboratory has continued these studies examining proximal and distal signaling from ephrinB1 that controls cell adhesion and cell movement. We recently found evidence that ephrinB1 signals via its intracellular domain to control retinal progenitor movement into the eye field by interacting with Dishevelled (dsh), and co-opting the planar cell polarity (PCP) pathway. Using biochemical analysis and gain or loss of function experiments, our data suggest that dsh associates with ephrinB1 and mediates ephrinB1 signaling via downstream members of the PCP pathway during eye field formation. thus, we have used the eye field as a model system for understanding how ephrinB1 controls cell movement.Most recently we have examined the mechanisms by which ephrinB1 affects cell-cell junctions. A body of evidence is emerging that shows a requirement for ephrin ligands in the proper migration of cells, and the formation of cell and tissue boundaries. These processes are dependent on the cellcell adhesion system, which playsa crucial role in normal morphogenetic processes duringdevelopment, as well as in invasion and metastasis19. AlthoughephrinB ligands are bi-directional signalling molecules, theprecise mechanism by which ephrinB1 signals through itsintracellular domain to regulate cell-cell adhesion in epithelialcells remains unclear. Here, we present evidence that ephrinB1associates with the Par polarity complex protein Par-6 (ascaffold protein required for establishing tight junctions) andcan compete with the small GTPase Cdc42 for association withPar-6. This competition causes inactivation of the Par complex,resulting in the loss of tight junctions. Moreover, the interactionbetween ephrinB1 and Par-6 is disrupted by tyrosinephosphorylation of the intracellular domain of ephrinB1. Thus,we have identified a mechanism by which ephrinB1 signallingregulates cell-cell junctions in epithelial cells, and this mayinfluence how we devise therapeutic interventions regardingthese molecules in metastatic disease.